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Splitomicin is a selective inhibitor of Sir2p with IC50 value of 60 μM and also a inhibitor of fMLP-induced free radicals with IC50 value of 40.79 ± 9.85 μM [1, 3].

Inhibition of the HDA of Sir2p was the most likely mechanism by which splitomicin caused its phenotypic changes. The direct target of splitomicin is Sir2p deacetylase activity. In addition, splitomicin specific inhibited fMLP-induced superoxide anion release.

In vitro, splitomicin inhibitd NAD+-dependent histone deacetylase activity of the Sir2 protein with an IC50 value of 60μM. By using a [3H]-acetylated histone H4 peptide and measuring the NAD+- dependent release of free [3H]acetate in the presence of whole yeast cell extract from an hst2 strain overexpressing yeast SIR2, a cell extract was obtained from a SIR2-overexpressing hst2 strain. The result established Sir2p deacetylase activity as a direct target of splitomicin. In addition, neutrophils induced by either fMLP (1 μM) or PMA (100 nM) were observed using a flow cytometer and the intracellular production of superoxide anions was investigated at different splitomicin concentrations. Splitomicin inhibited fMLP-induced Mac-1 expressionand increase cAMP levels in human neutrophils [1, 3].

Splitomicin's naphthoic moiety might be responsible for its inhibitory effects on platelets. By using washed human platelets, the inhibitory effects of splitomicin on platelet aggregation were studied and platelet aggregation and ATP release induced by thrombin (0.1 U/ml), collagen (2 μg/ml), arachidonic acid (0.5 mM), U46619 (2 μM) or ADP (10 μM) was monitored. Splitomicin inhibited platelet aggregation in a concentration dependent manner. Splitomicin increased cAMP and this effect was enhanced when splitomicin (150 μM) was combined with PGE1 (0.5 μM). The inhibitory mechanism of splitomicin on platelet aggregation may increase cyclic AMP levels via inhibition of cyclic AMP phosphodiesterase activity and subsequent inhibition of intracellular Ca ion mobilization, TXB2 formation and ATP release [2].

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